16, 17-oxido-11-dehydrocorticosterone and its esters



of from two to ten carbon atoms.

United States Patent This invention relates to steroids and in particular to 16,17-oxido-1l-dehydrocorticosterone esters, to processes for preparing these compounds and to intermediate compounds thus obtained. This application is a division of our application Serial No. 440,550, filed June 30, 1954, now US. Patent No. 2,809,967.

The compounds which are the subject of the invention are 16,17-ox ido-1lvdehydrocorticosterone esters which have the following general formula;

omit

wherein R is an acyloxy group having a chain length These compounds may be readily converted to valuable steroids such as cortisone. 1

The 16,17-,oxido-,1I-dehydrocorticosterOHfi esters are prepared by reacting 3 -ethylenedioxy-AWfi-pregnadiene- 11,20-dione (Compound I) with hydrogen peroxide in the presence of a base to produce 3:ethylenedioxy-16,17- oxido-A5-pregnene-l1,20-dione (Compound 11). This compound is then treated with an organic oxalate in the presence of a basic substance to form the corresponding Compound 11 ester of S-ethylenedioxy-l6,i7-oxido-A -pregnene-11,20- dione-Zl-oxalyl acid (Compound Ill) and also 17-hydroxy-Zlbcarbomethoxy-l6,21b- -pyrenone (Compound IV). The ester of 3-ethylenedioxy-l6,17-oxido-A -pregnene-l1,20-dione-21oxalyl acid is then hydrolyzed, treated with iodine in the presence of a base, and the resulting iodoketone is then reacted with a salt of; a carboxylic acid to form a 21-ester of 3-ethylenedioay-16,17e0Xid0 A -pregnene-2l-ol-i1,20-dione (Compound V). This latter compound may be subjected to hydrolysis to form the corresponding21-ester of 16,17-oxido-1.l:dehydrocg ticosterone (Compound VI).

As an alternate procedure, the 16,17-oxido-11-dehydrocorticosterone esters may be prepared byreacting 3- ethylenedioxy-A -pregnadiene-ll,20-dione (Compound I) with an organic oxalate in the presence of a basic substance to form an esterof 3 -.ethylenedioxy-A pregnadiene-lLZO-dione 21 oxalyl acid (Compound IX). This ester may be saponified to produce the corresponding acid (Compound X). The 3-ethylenedioxy-A pregna diene-l1,20-dione-2l-oxalyl acid is then treated with iodine in the presence of a basic substance and the resulting iodoketone is then reacted with a salt of a carboxylic acid to 'form a 21-ester of 3-ethylenedioxyeA fipregnadiene-Zl-ol-l1,20'-dione (Compound XI).' This latter compound may then be reacted with hydrogen 'to reductive dehalogenation to formthe cortisone ester.

The 2l-ester of 16,17-oxido-lli-dehydrocorticosterone (Compound VI) may be converted to the corresponding 21-este'r of cortisone (Compound VIII) by hydrolysis with a halogenv acid and reductive removal oi the 16-halogen These reactions may be chemically represented wherein R is an acyloxy group and R is an alkoxy group as follows:

CHI -BI Compound IX Compound X Compound XI CHaC-rC-R' (IJHQB H V I l v t ,0 Qompoundfll Compoundv oar! o- -ocm J I om =0 1 l o I w CompqundIV Q 7 V GompoundVlI Compound VIII -i The"3'-ethylenedioxy Ai -pregnadiene' 11,20-dione may beconverted. to '3-ethylenedioxy-16,l7-oxido-A r pregnene-ll,20-dione by treating with hydrogen peroxide in .the presence of a base. This reaction proceeds most -favorably in a solventv such as methanol, ethanol, propanol', butanol or the like. The basic substance may be ,-uct which may then be filtered from thesolution. The

product rnay be further purified by recrystallization.

The 3 ethylenedioxy-16,17-oxido-A -pregnene-11,20- dione is converted to the ester of 3-ethylenedioxy-l6,l7- oxido-A -pregnene-11,20-dione-21-oxalyl acid by reacting with an organic oxalate in the presencefiof abasic substance. This reaction is preferably carried out under anhydrous conditions. The reaction proceeds most favorably when carried out in a solvent for the reactants;

Suitable solvents are hexane, benzene, toluene, xylene,

the oxalyl ester compound with iodine in the presence of a base followed by alkaline cleavage to form the'corresponding 21-iodo compound. The reaction is most conveniently carried out in methanolic sodium methoxide although other alcohols and alkali metal alkoxides may be used. Orieequivalent of base and iodine are added and then after rapid decolorization is complete another equivalent of base is added. The reaction is complete after standing at 0 C. forone to twenty hours or at room temperature for one-half to fivev hours. After the reaction is complete the iodo compound may be recovered if desired by extracting with ether and then evaporating the ether. It is desirable in carrying out' the reaction to protect the reaction mixture and the product from light,

in order to avoid decomposition of the product. The

. iodo compound is then reacted with an alkali metal salt of a carboxylic acid to form the corresponding 21-ester petroleum ether, ether, dioxane, tetrahydrofuran and Y The basic substance may be any of the" of 3-ethylenedioxy-16,1fIoxido-A -pregnene-2l-ol-l1,2)0- dione. Typical examples of suitablemetal salts are sodium acetate, potassium acetate, sodium propionate and sodium'benzoate. This reaction is conveniently carried out by heating a solution of the iodo compound dissolved in a suitable solvent such as acetone under reflux with a potassium salt of a lower carboxylic acid for one-quarter to four hours. After completion of the reaction, the

sponding methyl or ethyl ester. The reaction proceeds favorably at room temperature in from 14 to 20 hours for completion although. other temperatures, such asfor 0 to C. may be used. The reaction product is t I one, This hydrolysis is readily achieved by treating with 1 an acid in a suitable solvent such as methanol, ethanol,

most conveniently separated from the reaction mixture by neutralizing the mixture by the addition of mineral or orgamc acid in theoretical amounts such as sulfuric,

hydrochloric, phosphoric or acetic acids or by the addi tion of an excess of an acidicbufier such as sodium di hydrogen phosphate and then extracting with a solvent such as chloroform. The extract containing the product 3 may then be concentrated to dryness to remove the exproduct is readily recovered by evaporating the solvent under diminished pressure, extracting the resulting residue with ether and then evaporating the ethereal extract.

The 2l-ester of 3-ethylenedioxy-16,17-oxido-A -pregnene-21-ol-1l,20-dione is hydrolyzed to form the corresponding 21-ester of 16,1]:07111071I-dChYdI'OCOI'tiCOStfiI- acetone'or tetrahydrofuran. Strong: acids such as hydrochloric acid, sulfuric acid, perchloricacid and ptoluene sulfonic acid used.in.dilute concentrations are preferred for eiiecting the hydrolysis. Temperatures ranging from about 20 to 100 C. are usually employed to accomplish the hydrolysis. At'the reflux temperature and then evaporating the ether solution to dryness.

5 of rthe solvent several minutes to one 1 9 .1 areordir arily adequate for completing the reaction. The reaction ture, following completion oi the reaction, may be diluted with water to precipitate the, desired Zl-ester of 16,17- oxido-ll-dehydrocorticosterone, which may be separated by filtration and then dried.

The 3-ethylenedioxy-A -pregnadiened1,2ihdione is reacted with an organic oxalate in the presence of a basic substance to form the corresponding ester of 3-ethyleuedioxy-a -pregnadiene-ll,2G clione-2l-oxalyl acid. This reaction is generally carried out under anhydrous tions. The reactants are preferably brought together in a solvent. Suitable solvents are hexane, benzene, toluene, xylene, petroleum ether, ether, dioxane, tetrahydrofuran and the like. The basic substances maybe any of the conventional bases such as, an alkali netal or its hydroidde, hydride or alkoxide, but, it is, preferred to use alkoxides, as for; example, sodium methoxide, sodium ethpxide, potassium methoxide or potassium ethoxide.

The oxalyl ester which is formed will depend on the particular oxalate selected. Any of the oxalates may be used but it is preferred, however, to use the lower dialkyl oxalates such as, dimethyl oxalate and diethyl oxalate, thereby forming the corresponding methyl or ethyl ester.

The reaction proceeds favorably at room temperature in from 14 to 20 hours although other temperatures, such as to 100 C., may be used. The reaction product is most conveniently separated from the reaction mixture by neutralizing the mixture by the addition of mineral or organic acid in theoretical amount such as sulfuric,

hydrochloric, phosphoric or acetic acids or by the addition of an excess of an acidic bufier such as sodium dihydrogen phosphate and then extracting with a solvent such as chloroform. The extract containing the product may then be concentrated to dryness to remove the excess oxalate.

The ester of 3-ethylenedioxy-A pregnadiene-ILZG- dione-2-glyoxalic acid may be'converted to the corre-' sponding acid by saponifying the ester. The saponification of the ester may be carried out by treating with any base such as an alkali metal hydroxide, carbonate, allroxide or the like. in the presence or" a solvent such asan ether or hydrocarbon with an alkali metal hydroxide. of such solvents are methyl ether, ethyl ether, methyl ethyl ether, toluene and benzene. formed may be treated with an acidic agent to form the 3- ethylene dioxy A -pregn'adiene-l1,20-dione-21-oxalyl acid. Any acid may be used for this step but it is preferred to use an acidic buffer such as sodium dihydrogen phosphate. The acids are particularly useful in themselves for separating the racemic steroids into their optical antipodes. As for example, upon intimately contacting the racemic steroid acid with an optically active base in a suitable solvent medium, the acidic compound reacts with the base to form a mixture of the d and i salts which may be separated by fractional crystallization from suitable solvents.

The 3 ethylenedioxy-A -pregnadiene-l1,20-dione-2loxalyl acid is converted to the 21-ester of 3-ethylenedioxy- A -pregnadiene-2l-ol-11,2G-dione. This conversion is carried out by first reacting the 3-ethylenedioxy-A -pregnadiene-l1,20-dione-21-oxalyl acid in a mildly alkaline solution such as aqueous disodium hydrogen phosphate with iodine. The reaction is completed by addinga strong base such as potassium hydroxide and allowing the reaction mixture to stand at approximately 6 to 25 C. for about one-half to twenty hours. The iodo compound may then be recovered if desired by extracting with ether It is desirable in carrying out the reaction to protect the reaction mixture and the product formed from light in order to avoid decomposition of the product. The iodo compound is then reacted with an alkali metal salt of a c tbosylic ac d to m th o spo n 21- 5 o y rv-A -p es adi nelMEMO-dime. Tha

The acid salt thus The reaction is preferably carried out in water Typical examples 1 1; assumes; o su h al fi sadism aceta e Potass um ac t sod um pr p uats. n sodium. be s atc. Thi reaction is preferably carried out by heating a, solution of the iodo compound dissolved in acetone under reflux with a potassium salt of alower carboxylic acid for about onequarter to four hours; The product may be readily recovered by evaporating the solvent under diminished pressure, extracting the resulting residue with ether and evaporating the ethereal extract.

The 21-ester of 3-ethylenedioxy-A l -Pregnadiene-Zl-olll,20-dione may be converted to the corresponding 21- ester'of 3-ethylenedioxy-16,17-oxidorn -pregnenee2l-ol 11, dione by treating with hydrogen peroxide in the presence of a base. This reaction proceeds most favorably in a solvent such as methanol, ethanol, propanoh butanol, or the like. The base may be; any of the basic substances such as alkali metal hydroxides, carbonates or bicarbonates. Typical examples of such compounds are potassium hydroxide, sodium hydroxide, sodium carbonate, sodiurn bicarbonate and potassium bicarbonate. The reaction proceeds most favorably at room temperature in from one to twenty hours. The product may then be recovered by diluting the reaction medium with water which precipitates the product which may then be filtered from the solution. '1 he product may be further purified by recrystallization.

The 21-ester of 3-ethylenedioxy-16,l7-oxido-A -pregnene-21-ol-l1,20-dione may be converted to the ZI-ester of 16 halo A pregnene-17a,21-diol-3,11,20-trione by cleavage of the oxido function with, hydrogen halides. Although hydrochloric and: hydroiodic acids may be used, it is preferred to use hydrobromic in the presence of a suitable solvent such as acetic acid or propionic acid.

The reaction proceeds rapidly at room temperature although increased reaction time and elevated temperature may be employed. The reaction product can be recovered Example 1 One milliliter of 2 N sodium methoxide was concen- ,trated to dryness and the residue washeated briefly at 100 C. under vacuum. To this dried sodium methoxide were added. 300 mg. of dime-thyl oxalate, 3 ml. of dry benzene and 250 mgcof 3-ethylenedioxy-Abl -pregnadiene- 1l,2 0-.dione. The reaction flask was stoppered tightly and Example 2 Saponification of the product of Example 1 by shaking a, benzene-ether solution'with 1 N potassium hydroxide sa he. pot ssium salt d t y a difi ion qt-tlie alkain s lu on. w th d lirdros n phosp at a d .tra'ction with. chloroform gave: the 3-ethylen'edioiyi ii pregnadienej-l1,20-dione-2l-oxalylj, acid, -m'elting point 1173-1839 c.-' de.)." f r i Example 3 i A solution of 2.25 grams of diso diumhydrogen phosphate in 50 ml. of water-was 'overlayered with 4ml.- of ether-containing 210 mg. of the methyles'ter of 3-ethylenedioxy-A -pregnadiene-l1,20-dione-2l-oxalyl acid. The

recation mixture was stirred rapidly and treated dropwise with a solution of-118 mg. of iodine in ml. of ether. Five minutes after the' addition of'iodine'was complete, 2 m1. of 1 N potassium hydroxide solution was-added. The mixture was stirred briefly atroom temperature, and

, then stored overnight in the icebox:- The reaction mixture was extracted with ether and the ether solution-was i dried and concentrated. The crude iodoketone obtained .in this fashion was dissolved in '7 ml. of acetone and heated unde'rireflux for one hour with500 mg. of moist potassium acetate: After removing the acetone under vacuum, water was, added and the organicmaterial was extracted with benzene-ether; 'The benzene-ether solution was dried and concentrated and the product was recovered by chromatography over alumina. Elution with ether-chloroform gave 3-ethylenedioxy-A -pregnadiene- 11,20-dione-21-ol-21-acetate purified by recrystallization from ether; melting. point 194-197" C.: 206208 C.;

A max. 236 me, E mol. 8,770.,

Example4 V v To a solution of 500 mg. of 3-ethyl enedioxy-A -pregnadiene-ll,20-dione in 30 ml. of methanol were added on ml. of'4 N sodiumhydroxide and 3 m1. of 30% hydrogen peroxide. After two'hours at room temperature, the reaction mixture was diluted to 100. mg. with icewater and the crystalline product which separated was collected on a filter, washed thoroughly with water and dried. .Recrystallization from benzene gave pure 3-ethylenedioxy-16,17-oxido A pregnene-l 1,20-dione, melting point 209-211 C.

Example 5 product by recrystallization from benzene gave methyl ester of 3-ethylenedioxy-16,17-oxido-A -pregnene-11,20- dione-Zl-oxalyl acid, melting point 177182 C., hmax.

287.5 III/L, E mol 8,090. Extension of the reaction'time' 'resulted in the production of the isomeric 17-hydroxy- 2lb-carbomethoxy-l6,2lb-pyrenone as a second product which could be purified by recrystallization from benzene. The melting point of the compound was 254 to 256 C., Amax. 288 m E mol. 8,000.

Example 6 A suspension of 340 mg. of the methyl ester of 3 ethylenedioxy-l6,17oxido A pregnene 11,20 dione. 21-oxalyl acid in 10 ml. of methanol was cooled to 0 C. and then with stirring treated first with 0.3 ml. of 2 N sodium methoxide solution and then a solution of 180 mg. of iodine in 10 ml. of methanol. After ten minutes at 0 C. an additional 0.4- ml. of 2N sodium methoxide was added and the reaction mixture was allowed to stir cold for two hours. Twenty milliliters of water was Iadded and the methanol was distilled under vacuum. *The aqueousv residue was extracted with chloroform and the chloroform solution was dried and concentrated. The-crude residual iodo-ketone was dissolved'in '15- m1.-

estates of "acetone" and :heated under reflux foronehour with one gram of moist potassium acetate; Inorganic salts were separated by .filtrat'ion and the filtrate was concentrated to dryness. The residue was dissolvedin chloroform, washed with water, dried and concentrated. Chromatography of the residue over alumina gave in the benzene eluate 3 ethylencdioxy 16,17 oxido A pregnene-21-ol-1l,20-dione 21-acetate; purified by re crystallization from ether, melting point 193-l94 C.

Example 7 Twenty milligrams of 3 -ethylenedioxy-16,17-oxido-A pregnene-21-ol-11,20-dione 21-acetate in 2,5 ml. of acetone containing 0.03 ml. of 78% sulfuric acid was heated under reflux for 15 minutes. The reaction m xture was diluted with water, theacetone was evaporated and the aqueous residue was extracted with ethyl acetate. The ethyl'acetate solution was dried over magnesium sulfate and concentrated. Crystallization of the residue from ethyl acetate gave pure dI-16,17-oxido-1l-dehydrocorticosterone acetate, melting point 2142l6 C,'

Example 8 Forty-five milligrams of 3-ethylenedioxy-16,17-oxido- A -pregnene-21-ol-l1,2O-dione 21-acetate was suspended in 0.4 ml. of acetic acid. The mixture waschilled to ca. 15 C. and treated with 0.1 ml. of 32% hydrogen bromide in acetic acid. Dissolution of the starting compound was soon followed by crystallization of the product. After 15 minutes, the mixture was cooled and the crystals were collected, washed with acetic acid and ether and dried. The product, 16-bromocortisone acetate, could be purified by recrystallization from ben zene; melting point 235-240 C. (dec.).

A solution of 35 mg. of l6-bromocortisone acetatein 3 ml. of ethanol was heated under refluxwith 15 mg. of Raney nickel for seven hours. After filtration from the catalyst, concentration of the ethanol gave dl-COliiSQBB acetate.

Any departure from the above description which conforms to the present invention is intended'to be included within the scope of the claims.

What is claimed is:

' 1. A compound having the formula wherein Ris selected from the class consisting of oxalyl and lower alkanoyloxy radicals.

2. A lower alkyl ester of 3-ethy1enedioxy-A -pregnadiene-l1,20 dione-21-oxalyl acid.

3.'Methyl ester of 3-ethylencdioxy-A -pregnadiene- 1 1,20-dione-2 l-oxalyl acid.

4. 3-ethylenedioxy A pregnadiene 11,20 dione- 21-oxalyl acid.

5. 3 ethylenedioxy A pregnadiene 21 ol- 1 1,20-dione-2l-acetate. 1

References Cited in the file of this patent UNITED STATES PATENTS,

,OTHER REFERENCES I Pincus 'et al.: The Hormones, vol. III, pages 549- 

1. A COMPOUND HAVING THE FORMULA 